The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Know the risks and potential benefits of clinical studies and talk to your health care provider before participating.
Read our disclaimer for details.

This study investigates the effects of a 12-week high-intensity interval training (HIT) on exercise tolerance, functional status and quality of life in patients with chronic heart failure with preserved ejection fraction (HFpEF), in comparison to a control group continuing to undergo usual care.

Condition or disease

Intervention/treatment

Phase

Heart Failure With Normal Ejection Fraction

Other: High-intensity interval training (HIT)Other: Usual care

Not Applicable

Detailed Description:

Heart failure (HF) with preserved ejection fraction (HFpEF) occurs in about 50% of all HF patients. Remodeling and fibrosis stimulated by inflammation appear to be main factors for the progression of HFpEF. Furthermore, iron deficiency (ID) has been recognized to be a common comorbidity in HFpEF. The lack of prognostic treatment options in HFpEF urgently calls for new therapeutic approaches. While beneficial effects of exercise training and iron substitution have been demonstrated in HF with reduced ejection fraction, they have not yet been evaluated in HFpEF. Therefore, the aim of this study is to investigate the effects of high-intensity interval training (HIT) in HFpEF patients with optimally adjusted iron values.

The proposed study will be a prospective, single-blind, randomized controlled trial in a primary care setting including 98 patients with stable HFpEF. Patients will undergo 3 study visits (a screening visit, a baseline visit and a post-intervention visit) including measurements of disease-specific biomarkers (using blood samples), cardiac and arterial vessel structure and function (using electrocardiogram, echocardiography and pulse wave velocity), exercise tolerance (using spiroergometry), habitual physical activity (using accelerometry) and QoL. After the screening visit, patients with a functional or absolute ID will undergo iron substitution until sufficient iron levels are reached (up to max. 12 weeks), in order to ensure comparable baseline conditions for the training intervention. The study examinations will be repeated after 12 weeks in both, initially iron deficient and non-iron deficient patients (baseline visit). Patients will then be randomized to either the intervention or control group, stratified by initial iron-deficiency status. The intervention group (n=49) will attend a supervised 12-week HIT on a bicycle ergometer, while the control group (n=49) will be advised to continue usual care and follow health recommendations for patients with chronic HF. After 12 weeks, the study measurements will be repeated in all patients (intervention and control group) in order to monitor the effects of the intervention (post-intervention visit). At 6 months, 1, 2 and 3 years after the last study visit, telephone interviews will be performed to assess medical outcomes and QoL.

Outlook: This study is expected to add important knowledge about the potential utility of a novel treatment strategy in HFpEF patients, which may help to improve both, QoL and functional status. Moreover, the analysed biomarkers might be able to provide further insight into prognosis and pathogenesis of HFpEF.

Study personnel involved in the study measurements will be blinded to whether patients are allocated to the intervention or control group. Furthermore, the statistician will be blinded to treatment allocation. To ensure blinding, the study measurements will be performed in different rooms and by different staff than those involved in the training intervention. It is not possible to blind participating patients and investigators performing the randomization and training sessions.

A 12-week HIT will be performed 3 times per week on a bicycle ergometer according to the protocol of Wisløff et al. In the first 4 weeks of the program, all sessions will consist of moderate continuous training (MCT) at 60-80% of peak heart rate (HRpeak) for 40 minutes in order that patients get used to exercising. For weeks 4-12, the following HIT protocol is intended: Patients will warm up for 10 minutes at moderate intensity (60-70% of HRpeak, Borg 11-13) before cycling four 4-minute intervals at high intensity (85-95% of HRpeak, Borg 15-17). Each interval will be separated by a 3-minute active pause at 60-70% of HRpeak (Borg 11-13). The training session will end with a 5-minute cool-down at moderate intensity (60-70% of HRpeak). Total exercise time will be 40 minutes.

Other: High-intensity interval training (HIT)

Supervised 12-week HIT 3 times per week on a bicycle ergometer.

Placebo Comparator: Usual care

Patients in the control group will continue to undergo usual care and be advised to follow health recommendations for patients with chronic heart failure according to an information leaflet of the Swiss Heart Foundation.

VO2peak will be measured by spiroergometry at the baseline and post-intervention visit: an incremental symptom-limited exercise test on an electronically operated bicycle ergometer (eBike, General Electric Company, Fairfield, Connecticut, USA) using a fixed ramp protocol (start at 10 watts, increase of 10 watts/minute) will be conducted. The test will be performed in an air-conditioned laboratory in the early afternoon under non-fasting conditions. After a 2-minute warm-up at 10 watts, patients will be instructed to pedal at a constant rate of 60 rpm to exhaustion or until signs of ischemia or serious cardiac arrhythmias appear. The exercise bout will be followed by a cool-down at 25 watts for 10 minutes or until HR is dropping down below 100 beats/minute. VO2peak will be defined as the highest value reached during exercise.

Secondary Outcome Measures :

Change in peak oxygen uptake (VO2peak) due to iron substitution [ Time Frame: -12 weeks and baseline (before and after iron substitution) ]

VO2peak will be measured by spiroergometry at the baseline and post-intervention visit: an incremental symptom-limited exercise test on an electronically operated bicycle ergometer (eBike, General Electric Company, Fairfield, Connecticut, USA) using a fixed ramp protocol (start at 10 watts, increase of 10 watts/minute) will be conducted. The test will be performed in an air-conditioned laboratory in the early afternoon under non-fasting conditions. After a 2-minute warm-up at 10 watts, patients will be instructed to pedal at a constant rate of 60 rpm to exhaustion or until signs of ischemia or serious cardiac arrhythmias appear. The exercise bout will be followed by a cool-down at 25 watts for 10 minutes or until HR is dropping down below 100 beats/minute. VO2peak will be defined as the highest value reached during exercise.

For measuring N-terminal prohormone of brain natriuretic peptide (NT-proBNP), Renin, Angiotensin-II (AT-2), Urocortin-2 (UCN-2), Osteopontin, Soluble ST2 (sST2), Galectin-3, Growth differentiation factor 15 (GDF-15), Copeptin, Big-Endothelin-1, Placental growth factor/Soluble Fms-like tyrosine-kinase 1 (PlGF/sFlt-1), High-sensitivity C-reactive protein (Hs-CRP), Interleukin 6 (IL-6) and Insulin-like growth factor-binding protein 7 (IGF-BP7), blood samples will be taken (in total 40 ml of blood) and immediately centrifuged, and the serum will be transferred to a separate tube, which will be frozen at approximately -80°C and stored in the central laboratory at the Cantonal Hospital Baselland in Liestal until the last patient will have completed the study procedures.

Change in echocardiographic parameters of the left ventricular systolic and diastolic function [ Time Frame: Baseline and 12 weeks ]

An echocardiography will be performed using a Full HD Color Doppler Ultrasound Scanner UF-890AG (Fukuda Denshi, Tokyo, Japan) by experienced echocardiographers blinded to the assignment of the patient to the intervention or control group, and independently analysed by cardiologists of the KSBL Liestal.

PWV will be measured at the same time as the echocardiographic parameters with the VaSera VS-2000 Vascular Screening System (Fukuda Denshi Co. Ltd, Tokyo, Japan) and evaluated by experienced blinded members of the study team.

The number of daily steps, physical activity level and time spent at different walking speeds will be measured by the AiperMotion 440 PC (Aipermon GmbH, Munich, Germany), a three-axis accelerometer that is attached to the belt on the left hip, on 7 consecutive days for at least 12 hours a day with the exception of the time spent for showering, bathing and sleeping. For recording daily activities and non-wearing periods, patients will be asked to keep a diary.

Change in NYHA functional class [ Time Frame: Baseline and 12 weeks ]

NYHA functional class will be determined according to the New York Heart Association classification.

Change in quality of life (QoL): The 36-Item Short Form Health Survey (SF-36) [ Time Frame: Baseline and 12 weeks ]

The SF-36 consists of 36 items, which are formatted as binary questions or as semantic 6-point differential scales. It refers to the past 4 weeks and includes 9 content areas concerning vitality, general health perception, physical functioning, social functioning, role limitations (emotional/physical problems), pain, mental health and health change.

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Patient-level anonymised datasets can be requested after completion of all planned analyses and publications from the study centre (anticipated by the end of 2020). Public access to the study protocol will be granted by publishing it in a scientific journal. Blood sample results will be shared on the Swiss Biobanking Platform.